Genetic Linkage in Lupus

狼疮的遗传连锁

• 批准号: 10220430
• 负责人: Leah Claire Kottyan
• 金额: $ 50.18万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220430
• 关键词: Alleles; Antibodies; Antibody Response; Antigens; Antinuclear Antibodies; Attention; B-Lymphocytes; Behavior; Binding; CD8-Positive T-Lymphocytes; Cells; ChIP-seq; Childhood; Complex; DNA Binding; Data; Data Analyses; Data Set; Disease; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Etiology; Foundations; Frequencies; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Risk; Genetic Transcription; Genome; Genomic Segment; Genomics; Human; Human Herpesvirus 4; Immune response; Infectious Mononucleosis; Knowledge; Location; Lupus; Major Depressive Disorder; Methods; Mutation; Neighborhoods; Nuclear Antigens; PC3 cell line; Patients; Process; Progress Reports; Publications; Publishing; Reagent; Regulation; Risk; Role; Screening procedure; Specificity; Systemic Lupus Erythematosus; Systems Biology; Technology; Testing; Variant; Viral Load result; Work; antigen processing; causal variant; cell transformation; cell type; disorder risk; exhaustion; experimental study; gene product; genetic linkage; genomic locus; infected B cell; programs; risk variant; transcription factor; transforming virus; virtual

Project Abstract There are 124 publications that establish 185 disease risk loci for the genetics of systemic lupus erythematosus (SLE) with robust supporting data. This is a completely different situation than when AI0274717 started 33 years ago as a search for genetic linkage. Now, in addition to the 185 risk loci we have strong circumstantial evidence for an etiologic role for Epstein-Barr virus (EBV) at the origin of SLE, especially considering the recently published powerful association between the location in the genome of transcription complexes containing the Latency III gene product, Epstein Barr Nuclear Antigen 2 (EBNA2) and the genetic risk loci of SLE. This association has been confirmed and extended to the at present known SLE risk loci. In addition, new data show that EBNA3C and EBNALP, both also EBV Latency III gene products, are also powerfully concentrated at the SLE risk loci, all three, EBNA2, -3C, & -LP, clustering together and in aggregate binding indirectly to more than half the known SLE risk loci. A set of human transcription factors and co-factors (TFs) tend to bind DNA at these same SLE risk loci. Our hypothesis is that many genetic mechanisms that cause SLE operate in the EBV transformed B cell, because of the EBV Latency III gene expression. Since ~90% of the plausibly causal variants in the 185 risk loci are in genomic regions, predicted to have regulatory function; therefore, the role of TFs promises to be important in the genetic mechanisms of SLE. What is missing, a serious gap in our knowledge, is the identify of the Target genes regulated by these risk variants. Given the unexpected, but dominating influence of the Latency III gene products in associations with the SLE risk loci, we conclude that the cell type in which to begin the systematic search for the disease relevant Target genes is the EBV-infected and transformed B cell. In Aim 1 we will focus on identifying Target genes in these cells for as many of the 185 SLE risk loci as possible with special attention focused on the involvement of EBNA2. In Aim 2 we will concentrate on the allelic differences in Target gene expression induced by the risk and non-risk alleles of SLE risk locus variants, again with special attention to the possible role of EBNA2. We have preliminary data that support our technical capacity to perform the experiments proposed and have constructed many of the reagents needed to perform the proposed experiments, which have been initiated. We will adapt high throughput systems biology methods to screen and explore the gene regulation of the 185 loci to build a foundation to evaluate the role EBNA2 has in SLE etiology relevant regulation. Extraordinary new commercially available methods will make the screening procedures proposed practical, feasible and affordable. If our hypothesis is correct and we demonstrate EBNA2-dependent mechanisms of gene regulation at the risk loci, then these would be nominated as potential causal mechanisms for the genesis of SLE. These results will lay the foundation for the important next step, to perturb the identified mechanism in ways that change the risk of developing SLE or that change the capacity of the illness to persist.

项目摘要 有124篇出版物建立了系统性红斑狼疮遗传学的185个疾病风险位点 (SLE)强大的支持数据。这与AI 0274717启动33年时的情况完全不同 是为了寻找基因联系现在，除了185个风险位点，我们有强有力的间接证据 EB病毒（EBV）在SLE起源中的病因作用，特别是考虑到最近发表的 在含有潜伏期III的转录复合物的基因组中的位置之间的强关联 基因产物、Epstein巴尔核抗原2（EBNA 2）和SLE的遗传风险位点。这种关联 已得到证实并扩展到目前已知的SLE风险位点。此外，新的数据显示，EBNA 3C 和EBNALP，都是EB病毒潜伏期III基因产物，也强烈集中在SLE风险位点，所有 三种，EBNA 2，-3C，& -LP，聚集在一起，间接结合超过一半的已知的 SLE危险基因座。一组人类转录因子和辅因子（TF）倾向于在这些相同的SLE风险中结合DNA。 的位点我们的假设是许多导致SLE的遗传机制在EBV转化的B细胞中起作用， 因为EB病毒潜伏期III基因表达。由于185个风险基因座中约90%的疑似因果变异 位于基因组区域，预测具有调节功能;因此，TF的作用很重要 SLE的遗传机制在我们的知识中，缺少的是对目标的识别， 受这些风险变体调控的基因。考虑到潜伏期III基因出乎意料的，但主导性的影响， 产品与SLE风险基因座相关，我们得出结论，开始系统性免疫应答的细胞类型 寻找与疾病相关的靶基因是EB病毒感染并转化的B细胞。在目标1中，我们将重点关注 在这些细胞中识别尽可能多的185个SLE风险位点的靶基因，特别注意 重点关注EBNA 2的参与。在目标2中，我们将集中于靶基因中的等位基因差异 SLE风险基因座变异体的风险和非风险等位基因诱导的表达，再次特别注意 EBNA 2的可能作用。 我们有初步的数据支持我们的技术能力，进行拟议的实验， 构建了许多进行已启动的拟议实验所需的试剂。我们 将采用高通量系统生物学方法筛选和探索185个位点的基因调控， 为评价EBNA 2在SLE病因相关调控中的作用奠定基础。非凡的新 商业上可获得的方法将使拟议的筛选程序切实可行和负担得起。 如果我们的假设是正确的，我们证明EBNA 2依赖的基因调控机制的风险， 位点，那么这些将被提名为SLE发生的潜在因果机制。这些结果将 为重要的下一步奠定基础，以改变风险的方式扰乱已确定的机制 或改变疾病持续的能力。